Vascular occlusion due to the pathological accumulation of blood components(platelets, fibrinogen, etc.) in the circulation, results in thrombotic disease, which is the number one killer in the industrialized world. Plasminogen activator inhibitor 1 (PAI-1) is a serpin that plays an important role in the control of normal and pathological thrombosis (clotting) and fibrinolysis (clot breakdown). PAI-1 is a mechanism based inhibitor of urokinase (uPA) and tissue type (tPA) plasminogen activators. PAI-1 prevents the formation of plasmin, thus inhibitingthe fibrinolytic system and promoting thrombosis in the vasculature and extravascular fibrin deposition seen in acute lung and pleural injury, lung, and cystic fibrosis, etc. High levels of PAI-1 are associated with a number of life threatening conditions such as myocardial infarction, sepsis, atherosclerosis, angina pectoris, pleural and acute lung injury and correlate with unfavorable outcomes in disseminated intravascular coagulation (sepsis), acute lung and pleural injury, and in a number of malignancies. Evaluation of the serpin reaction and mechanisms of PAI-1 neutralization, and the search for new PAI-1 inhibitors results in the improvement of fibrinolytic therapy. Understanding the molecular mechanisms governing fibrinolysis is an approach to personalizing fibrinolytic therapy and predicting its outcome based on the analysis of the bio-samples from a patient.

Current Projects/Lay Summaries:

I. Study of serpin/proteinase interactions and intermolecular mechanisms of modulation of serpin activity and stability. Current studies include understanding the mechanisms that control (i) the specificity of the serpin reaction; (ii) the modulation of PAI-1 activity via intermolecular interactions; (iii) the contribution of exosite interactions to serpin/proteinase reactions; (iv) thespontaneous inactivation of PAI-1. Recent results can be found in the references below: Papers 2, 6, 7, and Abstract 6.

II. Targeting PAI-1 in vivo to increase the efficacy of fibrinolytic therapy. Recently, we have validated active PAI-1 as a molecular target for fibrinolytic therapy in an animal model of pleural fibrosis (Paper 3, Abstract 8). A mechanism that controls the efficacy of fibrinolytic therapy with prourokinase (scuPA) has been proposed and evaluated (Paper 1; Abstract 7). Several intermolecular mechanisms of PAI-1 neutralization previously characterized in vitro were tested in vivo to determine the contribution of active PAI-1 to the efficacy of fibrinolytic therapy (Abstracts 2, 5). Targeting PAI-1 significantly improves the outcomes of fibrinolytic therapy with both scuPA and sctPA.

III. Bio-analytic approaches to personalized fibrinolytic therapy. Fibrinolytic therapy is focused on the activation of endogenous plasminogen to plasmin, providing sustained fibrinolytic activity. Accumulating data demonstrate that while the basic mechanisms governing endogenous fibrinolytic activity could be similar even between different species (Papers 1, 4; Abstracts 1, 4), their different manifestation in individuals could dramatically affect the outcome of fibrinolytic therapy. This project aims to develop an algorithm that would allow us to predict the results of fibrinolytic therapy for an individual, based on the analysis of a pattern of molecular signatures in bio-samples.

IV. Design and characterization of new inhibitors of PAI-1. At present, monoclonal antibodies (mAbs) are the most specific and selective inhibitors of PAI-1. However, therapeutic use favors the search for small (LMW) molecules that inhibit PAI-1 with similar efficacy. Our fundamental knowledge of serpin mechanisms builds a foundation for the development of new PAI-1 inhibitors, and their testing in animal models. Known mechanisms of PAI-1 inactivation are employed for (i) combinatorial selection of peptides specific for the epitopes of PAI-1 neutralizing mAbs, (ii) studies of additivity between different intermolecular mechanisms affecting PAI-1 activity, (iii) further minimization of PAI-1-specific ligands mAb (150 KDa) → Fab (40 KDa) → scFv (20 KDa) → peptide (1-2KDa)→ LMW inhibitors (0.5-1.5 KDa), and (iv) the generation and testing of new multivalent modulators of PAI-1.

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